The present disclosure relates to a composition for preventing or treating ototoxic hearing loss, sudden sensorineural hearing loss, and noise induced hearing loss that are caused by aminoglycoside-based antibiotic.
Hearing loss, which is also known as deafness, can be divided into conducive hearing loss and sensorineural hearing loss. The conducive hearing loss occurs when an external ear and a middle ear, which are organs responsible for transmission of sound, are infected with a disease such as inflammation, and the sensorineural hearing loss occurs when problems arise in a cochlea that is an organ responsible for detection of sound, auditory nerves that transmit sound into electric energy, and a brain that is an organ responsible for hearing and performs comprehensive roles including discrimination and understand of sound. Hearing loss is a common disease that appears in about 15 to about 20% of the population. In particular, the sensorineural hearing loss may be caused by an inflammatory disease, such as labyrinthitis or meningitis, noise, an ototoxic drug, an injury, such as a fracture of a temporal bond, presbycusis, a Meniere's disease, a disease associated with a metabolism, such as hypothyroidism, an ischemic brain disease, a blood disease, such as leukemia, neurological indisposition, such as multiple sclerosis, an immune disorder, a tumoral disease, such as acoustic tumor, or a bone disease.
An aminoglycoside-based antibiotic is one of representative ototoxic drugs, and examples thereof include streptomycin, kanamycin, gentamicin, neomycin, amikacin, tobramycin, netilmicin, dibekacin, and sisomycin. The aminoglycoside-based antibiotic is mainly used for gram-negative infection, which is not influenced by typical antibiotics, tuberculosis, or deep wound infection. The aminoglycoside-based antibiotic may have ototoxicity that causes dysfunction of hearing loss and balance in an inner ear, and side effects of nephrotoxicity. Such ototoxicity and side effects may occur when a subject takes an overdose of a drug or takes a drug for a long period of time. In some cases, ototoxicity may be also caused when a subject takes an appropriate dose of a drug for a short period of time. The ototoxicity of the aminoglycoside-based antibiotic is shown as a disorder of vestibular function in about 15% of users, and as hearing loss in about 10 to about 30% of users. In particular, the ototoxicity of the aminoglycoside-based antibiotic occurs in both ears in a form of severe hearing loss at a high frequency of about 4,000 hertz (Hz). Studies attempted to prevent and treat ototoxic hearing loss were mainly focused on antioxidant therapy having protective effects using an antioxidant. Here, it has been reported that vitamin E, aspirin, and N-acetylcysteine were found to be effective in reducing ototoxicity caused by the aminoglycoside-based antibiotic. However, it has been also reported that aspirin had adverse effects in promoting ototoxicity, or had problems in causing severe side effects on other organs.
An endoplasmic reticulum (ER) called an autophagosome is recently observed in a hair cell, and accordingly, an autophagy phenomenon and a correlation between the autophagosome and ototoxicity come into the spotlight. Rapamycin (RPM) is known to serve to block functions of a mammalian target of rapamycin (mTOR) which controls various factors involved in cell growth and division, and accordingly to induce autophagy, which is a new type of an apoptosis mechanism upon down-regulation of proteins of autophagy-related genes (Atg). Thus, RPM has been widely used as a representative autography inducer.
Thus, RPM receives the attention in studies for ototoxicity, and recently, relaxation effects of RPM against ototoxicity caused by an anticancer drug, cisplatin, have been disclosed (refer to non-patent document 1).
It is similar that both aminoglycoside and cisplatin are associated with ototoxicity upon generation of reactive oxygen species (ROS). However, in the case of aminoglycoside, it is known that aminoglycoside enters into auditory cells through a mechano-electrical transducer (MET) channel to be combined with iron (Fe2+), and accordingly, an aminoglycoside-Fe2+ complex obtained therefrom induces formation of ROS while causing damages to the auditory cells only.
However, in the case of cisplatin, it is known that cisplatin forms a monohydrate complex which generates nicotinamide adenine dinucleotide phosphat-oxidase 3 (NADPH oxidase 3, NOX-3), and accordingly, ROS is produced very excessively so that not only the auditory cells, but also surrounding support cells and nerve cells are also influenced by ROS. In addition, it has been reported that cisplatin induces apoptosis through a caspase-dependent pathway while aminoglycoside induces apoptosis through both a caspase-dependent pathway and a caspase-independent pathway. Regarding the occurrence of symptoms, auditory abnormalities appear with a delay for about a few days or weeks to a patient subjected to administration of aminoglycoside-based antibiotics. However, auditory abnormalities appear relatively quickly to a patient subjected to administration of cisplatin. Since there is obvious differences in the mechanism of ototoxicity between the two drugs, it cannot conclude that the drugs are preferable therapeutics for ototoxic hearing loss caused by the aminoglycoside-based antibiotic.
Therefore, the effects of the RPM on the ototoxic hearing loss caused by the aminoglycoside-based antibiotics need to be confirmed.